B03 CARFILZOMIB AND LENALIDOMIDE FOR PRIMARY PLASMA CELL LEUKEMIA: FINAL RESULTS OF THE PROSPECTIVE PHASE 2 EMN12/HOVON-129 STUDY FOR PATIENTS AGED ≥66 YEARS
Authors: P. Musto, M.C. Minnema, W.W.H. Roeloffzen, A. Capra, B. van der Holt, A. Juul Vangsted, A. Broyl, F. Schjesvold, T. Lund, T. Silkjaer, R. Benjamin, M. Grasso, K. Lung Wu, J. Caers, M. Cavo, R. Hájek, B. Bruno, A. Gadisseur, G. Pietrantuono, M. Offidani, L. Pour, P. Sonneveld, M. Boccadoro, N. van de Donk
Journal: HemaSphere (2023)

Introduction: Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with poor prognosis. The EMN12/ HOVON-129 study assessed carfilzomib and lenalidomide as first-line therapy in pPCL. Pts ≥18 years were enrolled, with different treatment for those 18-65 and ≥66 years. Here we report the results for pts ≥66 years. Methods: Inclusion criteria were newly diagnosed pPCL (>2x109/L circulating monoclonal plasma cells and/or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction and creatinine clearance <15 ml/min. There were no restrictions based on blood counts. Pts ≥66 years received eight 28-day induction cycles of carfilzomib-lenalidomide-dexamethasone (KRd; K: 20/36 mg/m2 days 1,2,8,9,15,16; R: 25 mg days 1-21; d: 20 mg days 1,2,8,9,15,16,22,23), followed by maintenance with KR (K: 27 mg/m2 days 1,2,15,16 for the first 12 cycles; then 56 mg/m2 days 1,15; R: 10 mg days 1-21/28 days) until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate, overall survival (OS), and toxicity. Results: From Oct 2015 to Aug 2021, we enrolled 61 pts with pPCL: 36 were ≤65 years and 25 ≥66 years. Among pts ≥66 years, median age was 71 years (range 66-84); 68% had bone disease; WHO performance status was 2 in 24% and 3 in 16% of pts. Median plasma cell percentage in bone marrow biopsy was 80% (10-100). Median peripheral blood plasma cell count was 3.8x109/L (range 2.0-52); median platelet count was 142x109/L (range 13-384); median GFR was 56 ml/min (range 24-95). Most of pts had high-risk disease features: 52% had elevated LDH; 20% del(17p), 4% t(4;14), 4% t(14;16), and 48% gain/amp(1q); 12% of pts had extramedullary plasmacytomas; 68% had ISS III and 40% Revised ISS III. At the data cut-off (July 1, 2022), among the 25 pts, 17 (68%) received the planned 8 cycles of induction treatment, achieving ≥ PR in 80%, ≥VGPR in 68%, and ≥CR in 32%; 16 pts (64%) received maintenance treatment. Best response on protocol was ≥PR in 80%, ≥VGPR in 68% and ≥CR in 36%; 3 out of 4 pts in CR who could be evaluated for minimal residual disease (MRD) achieved MRD negativity (10-5) by flow cytometry. With a median follow-up of 24.6 months (range 7.9-59.6), median PFS was 13.8 months (95% CI 9.2-35.5); median OS was 24.8 months (95% CI 14-NR - 16 deaths: 8 disease progression, 2 unknown, 1 pneumonia, 1 sepsis, 1 systemic aspergillus infection, 1 small intestinal SPM, 1 disseminated intravascular coagulation, 1 respiratory failure due to COPD exacerbation). Toxicity rate was 36% both for G3 and for G4 events. G3 and G4 hematologic toxicity rates were 8% and 12%. Infections (20% and 16%) and respiratory events (16% and 4%) were the most common G3 and G4 non-hematologic toxicities. Twenty-two pts (88%) discontinued treatment, mainly because of progression (13 pts, 59%). Conclusions: KRd is a potent strategy to control pPCL in pts ≥66, with not negligible, but generally manageable, treatment-related toxicities. Besides a significant PFS improvement, median OS substantially doubled compared to what has been reported in recent retrospective studies (see the only other prospective trial with Rd) in transplant ineligible, elderly pts with pPCL (Musto P et al. Leukemia. 2014).